Turner Syndrome Minipuberty Study

Infertility, Female Clinical Trial

— Minipuberty  

Official title:

Turner Syndrome Minipuberty Study A Prospective, Descriptive Cohortstudy

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT04189406
• Other study ID #: 2019-5955
• Status: Recruiting
• Start date: February 1, 2020
• Est. completion date: December 1, 2024

Study information

• Verified date: March 2023
• Source: Radboud University Medical Center
• Contact: Sanne vd Coelen, MD
• Phone: +31243098078
• Email: sanne.vandercoelen[@]radboudumc.nl
• Is FDA regulated: No
• Study type: Observational

Clinical Trial Summary

Rationale: Due to accelerated germ cell loss, infertility is a major problem in girls with Turner syndrome (TS). Therefore, cryopreservation of ovarian tissue or oocytes before exhaustion of the ovarian reserve may preserve fertility in patients with TS. However, in the majority of females with TS , the ovarian reserve is exhausted before the age of menarche. Early markers indicating and predicting the ovarian reserve are necessary. During mid-childhood the hypothalamic-pituitary-gonadal (HPG) axis is quiescent and gonadotropins are usually unmeasurable. Nonetheless, this axis is active during infancy. Therefore, gonadotropins are measurable with peak values at 3 months of age and with lower (but still measurable) values at 9 months of age, in a period called the minipuberty. The aim of this study is to find markers of ovarian capacity, during the minipuberty, in order to predict ovarian reserve in the future.

Objective: The hormonal range of LH, FSH, AMH, inhibin B, testosterone and estradiol in girls with TS during the minipuberty and the relation of the hormone serum levels with the karyotype.

Study design: A prospective, cohort study with a duration of 3 years. Study population: Girls with a pre- or perinatal diagnosis TS who are born in a medical centre in the Netherlands during the duration of the study

Main study parameters/endpoints: Serum levels of FSH, LH, AMH, inhibin B, testosterone and estradiol at the age of 3 and 9 months.

Description:

Nature and extent of the burden and risks associated with participation, benefit and group relatedness:

The subjects will have twice an extra venapunction for collection of 3.5mL blood during their infancy, which is not stated in the guidelines for TS. There is very little risk for adverse events associated with this blood sample collection, however it is an extra procedure. The outcome parameters will not be helpful for individual study participants, however they are likely to help clinicians and researchers in understanding how the ovarian function operates develops in girls with TS. Furthermore, these markers could be used to estimate the ovarian reserve and the urgency of fertility preservation in young females with TS. This information could help clinicians, patients and their parents in decision making.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 30
• Est. completion date: December 1, 2024
• Est. primary completion date: December 1, 2024
• Accepts healthy volunteers: Accepts Healthy Volunteers
• Gender: Female
• Age group: 1 Month to 3 Months

Eligibility

Inclusion Criteria:

In order to be eligible to participate in the TS group of this study, a subject must meet all of the following criteria:

• A diagnosis of TS before the age of three months;

• Girls with a diagnosis of classic TS or other variants (i.e. 45,X, 45,X/46XiXq, 45,X/46,XY, 45,X/46,XX, 45,X/47,XXX, 45,X/46,X,r(X), 46,XiXq, other);

• Whose parents have agreed to participate in the study through a signed written informed consent form.

In order to be eligible to participate in the control group of this study, a subject must meet all of the following criteria:

• No diagnosis of TS or any other diagnosis that might affect the HPG axis;

• Girls that will have a blood collection within their usual care at 3 months and at 9 months of age.

• Whose parents have agreed to participate in the study through a signed informed consent form.

Exclusion Criteria:

A potential subject who meets any of the following criteria will be excluded from participation in this study:

• Any other diagnosis besides TS that might affect the HPG axis;

• Ovarian surgery in the medical history;

• Critical illness;

• The use of medication affecting the HPG axis (e.g. estrogen suppletion therapy)

Related Conditions & MeSH terms

• Chromosome Disorders
• Gonadal Dysgenesis
• Infertility
• Infertility, Female
• Menopause, Premature
• Ovarian Diseases
• Premature Birth
• Premature Menopause
• Premature Ovarian Failure
• Primary Ovarian Insufficiency
• Sex Chromosome Disorders
• Syndrome
• Turner Syndrome

Intervention

Other:
• Venapunction
A blood sample of 3.5 mL (0.2 mL serum for FSH and LH, 0.15 mL serum for E2, 0.15 mL serum for T, 0.15 mL serum for AMH and 0.25 mL serum for Inhibin B) will be collected of all girls with TS at 3 months and 9 months of age. For the girls with TS, this will be collected with an extra venapuncture during a regular outpatient visit within the usual care.

Locations

Country	Name	City	State
Denmark	Righospitalet, University of Copenhagen	Copenhagen
Germany	Universitätsklinikum der Ruhr-Universität Bochum	Bochum
Germany	Justus-Liebig Universität Giessen	Gießen
Germany	Universitätsklinikum Tübingen	Tübingen
Netherlands	Amsterdam University medical center	Amsterdam
Netherlands	University medical center Groningen	Groningen
Netherlands	Leiden University medical center	Leiden
Netherlands	Maastricht University medical center	Maastricht
Netherlands	Radboud University Medical Center	Nijmegen	Gelderland
Netherlands	Erasmus University medical center	Rotterdam
Netherlands	University medical Center Utrecht	Utrecht
Poland	Medical university of Silesia	Katowice
Sweden	University hospital of Umea	Umeå

Sponsors (1)

Lead Sponsor	Collaborator
Radboud University Medical Center

Countries where clinical trial is conducted

Denmark,  Germany,  Netherlands,  Poland,  Sweden, 

References & Publications (11)

Bernard V, Donadille B, Zenaty D, Courtillot C, Salenave S, Brac de la Perriere A, Albarel F, Fevre A, Kerlan V, Brue T, Delemer B, Borson-Chazot F, Carel JC, Chanson P, Leger J, Touraine P, Christin-Maitre S; CMERC Center for Rare Disease. Spontaneous fertility and pregnancy outcomes amongst 480 women with Turner syndrome. Hum Reprod. 2016 Apr;31(4):782-8. doi: 10.1093/humrep/dew012. Epub 2016 Feb 13. — View Citation

Borgstrom B, Hreinsson J, Rasmussen C, Sheikhi M, Fried G, Keros V, Fridstrom M, Hovatta O. Fertility preservation in girls with turner syndrome: prognostic signs of the presence of ovarian follicles. J Clin Endocrinol Metab. 2009 Jan;94(1):74-80. doi: 10.1210/jc.2008-0708. Epub 2008 Oct 28. Erratum In: J Clin Endocrinol Metab. 2009 Apr;94(4):1478. Birgit, Borgstrom [corrected to Borgstrom, Birgit]; Julius, Hreinsson [corrected to Hreinsson, Julius]; Carsten, Rasmussen [corrected to Rasmussen, Carsten]; Maryam, Sheikhi [corrected to Sheikhi, Maryam]; Gabriel, Fried [corrected to Fried, Gabriel]; Vi. — View Citation

Bryman I, Sylven L, Berntorp K, Innala E, Bergstrom I, Hanson C, Oxholm M, Landin-Wilhelmsen K. Pregnancy rate and outcome in Swedish women with Turner syndrome. Fertil Steril. 2011 Jun 30;95(8):2507-10. doi: 10.1016/j.fertnstert.2010.12.039. Epub 2011 Jan 22. — View Citation

Burgoyne PS, Baker TG. Perinatal oocyte loss in XO mice and its implications for the aetiology of gonadal dysgenesis in XO women. J Reprod Fertil. 1985 Nov;75(2):633-45. doi: 10.1530/jrf.0.0750633. — View Citation

Fechner PY, Davenport ML, Qualy RL, Ross JL, Gunther DF, Eugster EA, Huseman C, Zagar AJ, Quigley CA; Toddler Turner Study Group. Differences in follicle-stimulating hormone secretion between 45,X monosomy Turner syndrome and 45,X/46,XX mosaicism are evident at an early age. J Clin Endocrinol Metab. 2006 Dec;91(12):4896-902. doi: 10.1210/jc.2006-1157. Epub 2006 Sep 12. — View Citation

Huang JY, Tulandi T, Holzer H, Lau NM, Macdonald S, Tan SL, Chian RC. Cryopreservation of ovarian tissue and in vitro matured oocytes in a female with mosaic Turner syndrome: Case Report. Hum Reprod. 2008 Feb;23(2):336-9. doi: 10.1093/humrep/dem307. Epub 2007 Dec 2. — View Citation

Johannsen TH, Main KM, Ljubicic ML, Jensen TK, Andersen HR, Andersen MS, Petersen JH, Andersson AM, Juul A. Sex Differences in Reproductive Hormones During Mini-Puberty in Infants With Normal and Disordered Sex Development. J Clin Endocrinol Metab. 2018 Aug 1;103(8):3028-3037. doi: 10.1210/jc.2018-00482. — View Citation

Lanciotti L, Cofini M, Leonardi A, Penta L, Esposito S. Up-To-Date Review About Minipuberty and Overview on Hypothalamic-Pituitary-Gonadal Axis Activation in Fetal and Neonatal Life. Front Endocrinol (Lausanne). 2018 Jul 23;9:410. doi: 10.3389/fendo.2018.00410. eCollection 2018. — View Citation

Pasquino AM, Passeri F, Pucarelli I, Segni M, Municchi G. Spontaneous pubertal development in Turner's syndrome. Italian Study Group for Turner's Syndrome. J Clin Endocrinol Metab. 1997 Jun;82(6):1810-3. doi: 10.1210/jcem.82.6.3970. — View Citation

Stochholm K, Juul S, Juel K, Naeraa RW, Gravholt CH. Prevalence, incidence, diagnostic delay, and mortality in Turner syndrome. J Clin Endocrinol Metab. 2006 Oct;91(10):3897-902. doi: 10.1210/jc.2006-0558. Epub 2006 Jul 18. — View Citation

Sutton EJ, McInerney-Leo A, Bondy CA, Gollust SE, King D, Biesecker B. Turner syndrome: four challenges across the lifespan. Am J Med Genet A. 2005 Dec 1;139A(2):57-66. doi: 10.1002/ajmg.a.30911. — View Citation

* Note: There are 11 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Defining the LH range in blood during minipuberty in girls with TS at 3 months of age and at 9 months of age	LH (luteinizing hormone) will be collected with a venapuncture and analysed with the Elecsys method on the Cobas E801system of Roche.	1 year after venapuncture
Primary	Defining the FSH range during minipuberty in girls with TS at 3 months of age and at 9 months of age	FSH (follicle stimulating hormone) will be collected with a venapuncture and analysed with the Elecsys method on the Cobas E801system of Roche.	1 year after venapuncture
Primary	Defining the AMH range during minipuberty in girls with TS at 3 months of age and at 9 months of age	AMH (Anti-Müllerian hormone) will be collected with a venapuncture and analysed on the Access of Beckman Coulter.	1 year after venapuncture
Primary	Defining the estradiol range during minipuberty in girls with TS at 3 months of age and at 9 months of age	estradiol will be collected with a venapuncture and analysed with the LCMSMS analysis method.	1 year after venapuncture
Primary	Defining the testosterone range during minipuberty in girls with TS at 3 months of age and at 9 months of age	testosterone will be collected with a venapuncture and analysed with the LCMSMS analysis method.	1 year
Primary	Defining the inhibin B range during minipuberty in girls with TS at 3 months of age and at 9 months of age	inhibin B will be collected with a venapuncture and analysed with the GEN II ELISEA of Beckman Coulter.	1 year after venapuncture
Secondary	Patient's karyotype vs LH	The association between patient's karyotype and LH level at 3 months of age and 9 months of age	1 year after venapuncture
Secondary	Patient's karyotype vs FSH	The association between patient's karyotype and FSH level at 3 months of age and 9 months of age	1 year after venapuncture
Secondary	Patient's karyotype vs AMH	The association between patient's karyotype and AMH level at 3 months of age and 9 months of age	1 year after venapuncture
Secondary	Patient's karyotype vs estradiol	The association between patient's karyotype and estradiol level at 3 months of age and 9 months of age	1 year after venapuncture
Secondary	Patient's karyotype vs testosterone	The association between patient's karyotype and testosterone level at 3 months of age and 9 months of age	1 year after venapuncture
Secondary	Patient's karyotype vs inhibin B	The association between patient's karyotype and inhibin B level at 3 months of age and 9 months of age	1 year after venapuncture